Society for Endocrinology UK Guidance on the Initial Evaluation of a Suspected Difference or Disorder of Sex Development (Revised 2021)

S. Faisal Ahmed; John Achermann; Julie Alderson; Naomi S. Crouch; Sue Elford; Ieuan A. Hughes; Nils Krone; Ruth McGowan; Talat Mushtaq; Stuart O'Toole; Leslie Perry; Martina E. Rodie; Mars Skae; Helen E. Turner


Clin Endocrinol. 2021;95(6):818-840. 

In This Article

The Role of the Clinical Geneticist

Establishing a specific molecular diagnosis is helpful in the clinical management of cases and in offering accurate genetic counselling for the family. In those cases, where a clear steroidogenic defect has been identified biochemically, targeted single-gene analysis will confirm the diagnosis in most cases. Whilst the yield from diagnostic genetic testing maybe less than 50% in those who are 46, XY DSD and have no clear abnormality of steroidogenesis, with ongoing advances in genomic medicine,[52] the ability to better diagnose, predict and treat disease is anticipated to transform many aspects of care. For a significant number of individuals with a DSD, its utility may reside in ending diagnostic uncertainty and delivering personalized care.

Diagnostic genetic laboratories are moving from single-gene sequencing to high-throughput sequencing (HTS) assays (parallel testing), designed to sequence multiple DSD-related genes on a targeted panel in one analysis or through whole genome or exome sequencing (WGES) with predetermined filters that target DSD-related genes.[6,53] A targeted panel is advantageous as it yields high-quality coverage of the genes of interest, whilst minimizing the risk of incidental findings. Recent surveys of practice show the increasing use of HTS at an earlier stage of the diagnostic pathway in XY DSD[6] and with greater familiarity with this approach, as well as faster turnaround times, it is clear that practice is changing, such that, the choice of second-line endocrine investigations may be influenced by the results of the genetic analysis.[54]

The clinical geneticist at the specialist DSD centre can evaluate complex genetic syndromes and advise which genetic testing technique is appropriate and cost-effective for each clinical situation, following urgent confirmation of chromosomal sex. Initial testing is usually performed by quantitative fluorescence polymerase chain reaction (QFPCR) due to the rapid turnaround time and followed by chromosome analysis, either by karyotype, or more commonly, microarray, which identifies copy number variation (Figure 2). With the advent of targeted panels and WGES, more extensive biochemical and radiological investigations might be reserved until answers from analysis are obtained, with the potential to avoid further costly and invasive investigations. However, there are existing challenges in bringing HTS and WGES into mainstream practice.[53,54] Pre-test counselling needs to be broader, to cover all potential test outcomes, including the identification of gene variants of uncertain significance (VOUS) whilst explaining the limitations of this approach such as the variable coverage of the genes of interest in WGES. In addition, in line with international recommendations, patients and parents should be informed about the possibility of unsolicited findings of medically relevant disease variants. In NHS England, diagnostic genetic testing for DSD is included in the National Genomic Test Directory ( and in both England and Scotland it is provided through a network of NHS genomic laboratory centres. Diagnostic interpretation of the genetic findings requires a very careful and methodical approach and, to deliver a high-quality service, centres that provide a diagnostic genetic service for DSD should have detailed phenotypic information in addition to the genetic findings and which can be discussed at a regular meeting of a diagnostic board and which, as a minimum, consists of the clinical geneticist, the molecular geneticist, the clinical biochemist and the paediatric endocrinologist with a special interest in DSD at the diagnostic centre.[54] This diagnostic board should have the capacity to review their own activities and remain up to date with continuing advances in this field.

Figure 2.

An integrated pathway for genomic and phenotypic evaluation of DSD. VOUS—variant of unclear significance. A multidisciplinary diagnostic team that has detailed knowledge of the DSD field as well as the diagnostic tools plays a central role in the diagnostic process

Close involvement of the clinical genetics service can ensure that the MDT covers all aspects of genetic counselling including provision of information to the family, the mode of inheritance of the disorder and the choices or options available for dealing with this risk. Established links with the clinical genetics service are also useful when considering prenatal testing or interventions such as steroid hormone therapy in CAH or interruption of pregnancy. As the scope for non-invasive prenatal diagnosis (NIPD) using free floating foetal DNA continues to increase, the close involvement of the clinical geneticist at a very early stage in at-risk pregnancies will become even more important.[55] Abnormalities of sex chromosomes are identified in approximately 1% of all pregnancies that undergo prenatal karyotype and although 40% of these pregnancies may be associated with a termination, early referral for genetic counselling seems to be associated with a lower likelihood of termination.[56]